Image post 6: spinal cord cell reaches for its neighbor

While many posts from The Mix feature a science story, we also share images coming out of UAB research. Below is a description of what we are looking at and related hints about how the brain forms in the womb. 

Pictured here is one star-shaped astrocyte "reaching out" to another in a dish. The most abundant cell type in the brain and spinal cord, astrocytes are not nerve cells, but instead provide support, nutrients and protection to nerve cells. Recent work has shown that astrocytes help to shape the messages being passed from nerve cell to nerve cell, and that problems with astrocyte function may throw off nerve cell performance.

In her research, Michelle Olsen, Ph.D., assistant professor in the UAB Department of Cell, Developmental and Integrative Biology, seeks to determine how the overlap between nerve cells and astrocytes contributes to normal brain development, and to brain abnormalities when something goes wrong.

Dr. Olsen's experiments with isolated cells seek to model processes underway in the brain as it forms during development. Nerve cells are known to put out "roots" that reach out, find nearby cells and link up to form signaling networks. The above picture suggests that astrocytes do something similar.

Named for their star shape, astrocytes put out extensions that wrap around synapses, the gaps between nerve cells in signaling pathways. Each nerve cell in a pathway sends an electric pulse down itself until it reaches a synapse, a gap between itself and the next cell in line. When it reaches the cell's end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Arriving at the other side, they cause the downstream nerve cell to “fire” and, depending on the synapse type, to either pass on or stop the message.

In this way, each synapse between nerve cells “decides” whether or not a message continues down that pathway. The balance of messages passed on (excitation) and messages halted (inhibition) is crucial to brain function. One theory has it that astrocytes influence that balance at synapses with their own set of extensions and transmitters.

Dr. Olson captured the image using an inverted Zeiss Observer microscope. 

Mind-blower: epigenetics makes memories

Do you remember your five-year-old birthday party? How about your wedding? Emerging science argues that you can do so because those experiences turned off genes at the time in a certain set of nerve cells in your brain. Stranger still, nerve cells may have this capability because they have re-purposed epigenetic mechanisms that other human cells use to "remember who they are."

To back up for a moment, epigenetic mechanisms are chemical changes that turn genes on and off without changing the genes encoded in DNA that we inherit from our parents. Research in recent years has established that they lend an extra layer of regulatory finesse to human genetics and make our complexity possible.

Epigenetics first made a splash in developmental biology. Researchers realized that while we have the same set of genes in every one of our cells, we develop 250 different cell types by the time we are born. Epigenetic mechanisms switch off a different set of genes (and leave a certain set on) in each cell type to result in the 250 types.

Stem cells that become bone or blood or liver cells as we develop "remember" their specialized nature, and they pass that memory on to their descendants as they divide and multiply in the constant turnover under way in most human organs.

This genetic memory is known to be accomplished by epigenetic mechanisms like methylation, the chemical attachment of a methyl group (one carbon and three hydrogens) to certain spots on the DNA chain. The process can turn surrounding genes off (prevent gene expression), while demethylation can turn them back on in an ongoing back and forth.

It really gets fascinating when you consider that the nerve cells making up the brain, unlike nearly every other human cell type, never divide and multiply, and so they never pass on genetic memory. One theory on this is that nerve cells have put their genetic memory mechanisms to another purpose: remembering.

Most of this is theoretical of course, and it is the subject of intense study in the lab of David Sweatt, Ph.D., chair of the UAB Department of Neurobiology and director of the Evelyn F. McKnight Brain Institute here. He sat down with The Mix to discuss his presentation at a recent UAB Epigenetics Symposium about how nerve cells may have evolved to store memories.




Show notes for the podcast:

1:47 Sweatt's lab explores the role of epigenetics in the adult human brain. That has required a re-definition of epigenetics, a science once thought pertinent only to cells that divide and multiply, and that pass on epigenetic marks to their descendants. Nerve cells in the brain do not divide, multiply or turn over as a population, and yet, epigenetics mechanisms are at work. The field now recognizes that such mechanisms contribute to learning and memory.

4:14 The genetics and epigenetics of inheritance has finally answered one of the most long-standing questions in human history: how are traits passed down from parents to children? Epigenetics in neurobiology is also answering another longstanding, philosophical question: What makes us who we are? It turns out that epigenetic mechanisms "sit at the interface" of nature (genes) and nurture (environmental factors make epigenetic mechanisms that turn genes on and off).

5:58 Epigenetics have provided for scientists a fundamental answer for how a single transient experience can make a permanent change in the biochemistry of the brain. It is no small thing that we are now beginning to understand this once-mysterious process.

8:10 Methylation is the mechanism that silences perhaps half or three-quarters of the genes in the human genome to make a nerve cell a nerve cell. Those changes are life-long, and so that set of silenced genes is the same in that family of cells for a lifetime.

12:02 A foundational discovery made in other labs in recent years is that epigenetic changes to nerve cells are necessary for humans to remember things for the long term. Once the field knew that, they could begin to try to understand the mechanisms.

12:35 If anyone who is listening to this podcast today remembers it tomorrow,  it will be because of changes in the genes being expressed in the nerve cells of their brains as they listen. There is a continuous, dynamic interplay between our experiences and the parts of our genes recording memories. Epigenetic mechanisms are powerful regulators of gene transcription and translation, and appear to have been applied by evolution to the problem of storing memories.

13:22 If evolving nerve cells could talk, they might have said, "OK, I have to control which genes are turned on and off in certain nerve cells to store memories, what is the toolbox I have at hand to accomplish this?" It's the same toolbox of epigenetic mechanisms it uses to control gene expression in general.

13:35 Methylation has been been mentioned as part of the toolbox. Then there is histone acetylation. DNA does not just float around in the nuclei of human cells, but is instead wrapped around protein "spools" called histones that help to organize, protect and regulate them as part of a larger package called chromatin. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. Attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible. In addition, there is phosphorylation and ubiquitination, processes that now appear to regulate both chromatin in general and behavioral memory formation.

14:51 With environmental factors (sunlight, smoking and pollution) known to make epigenetic changes, many labs are trying to determine whether such changes have roles in many diseases. Humans have a protective compartment surrounding their brains that screens out many toxins called the blood-brain barrier.

16:23 Sweatt's presentation at the UAB epigenetics symposium discussed how he is working to determine the exact biochemical mechanisms by which methylation is changing the firing patterns of nerve cells to endow networks of nerves with the ability to store memories. What are the exact and ongoing patterns of active methylation and demethylation as the brain reacts to sensory experiences?

18:00 To study the process of memory formation, Sweatt's lab examines certain classes of basic memories that we share, presumably, with study animals like mice. For instance, to survive, our animal ancestors would have had to be able to remember which places were dangerous and which offered food or security (spatial recognition of surroundings).

19:02 Humans appear to have "place cells" in our hippocampus, the part of the brain that tells you where you are and where you have been. When you walk into a new room, or even a new place in a room, a particular set of hippocampal neurons fires in certain patterns in such a way that allows the brain to record a 3D map of that place. Different cells fire when you are in different places. One experiment under way in Sweatt's lab is seeking to test whether certain DNA methylation patterns enable those cells to record that sense of place.

21:27 All this research is ultimately aimed at understanding the normal brain so as to come up with new treatments for those with disorders that affect memory (dementia, Alzheimer's, etc.) and learning. Sweatt's lab and many others are seek to build the framework for the development of new molecular targets for new kinds of drugs.

The previous three podcasts in this epigenetic series were Epigenetics has impact on health beyond DNA, Epigenetics, aging and cancer and Obesity, exercise and epigenetics: no excuses.

Dr. Sweatt’s research is largely funded by the McKnight Brain Research Foundation.

Epigenetics has impact on health beyond DNA

As a science writer, I struggle to translate complex ideas like genetics into straightforward language.  Having covered genes many times over the years, I have come to depend on a few handy stock sentences that I recycle in story after story:

• The blueprint for the human body is encoded in genes, many of which hold the information necessary for the building of one or more proteins. 
• Gene expression is the process by which information stored in genes is converted into proteins, the workhorse molecules that make up the body’s structures and carry its signals. 
• Human genetic material includes about 3 billion bases, the “letters” that make up the DNA code containing genetic instructions.

Then about seven years ago, research surfaced that required the crafting of a new group of stand-by sentences. It turned out that, while genes were important, they represented just one part of a more complex human genomic system. Genes, the specific batches of code directly for the construction of proteins, were found to comprise just two percent of human DNA. Then humans were found to have one-fifth as many genes as wheat. What made us so complex then if not our genes alone?

The explanation was that we put the same genes to many uses with the help of complex regulatory mechanisms that govern when, where and to what degree our genetic material is accessed and activated. Some of these functions are performed by myriad non-gene DNA snippets called regulatory elements.

Still other recently discovered mechanisms contribute further to our genetic regulatory finesse, and without changing the instructions encoded in the DNA we get from our parents. Such changes represent the province of the emerging field of epigenetics and the focus of a recent UAB Epigenetics Symposium. The Mix – the UAB research blog – interviewed some of the presenters and is featuring the talks in a series.

Our guest for this podcast is Bruce Korf, M.D., Ph.D., chair of the UAB Department of Genetics, one of the organizers of the symposium.

Show notes from the Podcast:

:40 Epigenetics is defined as changes in human gene expression caused, not by changes in the order of base pair "letters" making up the DNA code (such changes are called mutations), but instead by chemical actions that affect the ability of the instructions encoded in a given stretch of DNA to be read and followed.

1:15  Researchers have long known that changes that turn genes on or off play a critical role in fetal development and in the response of humans to their environment, but not what controls those changes. It's now becoming clear that epigenetic mechanisms can permanently silence a gene, for instance, in a particular cell type.

2:01  Cells divide and multiply as the human fetus develops.  Epigenetic changes do not just turn off a gene at a particular point in time, they turn it off in that cell and in all its descendants. That makes such changes useful a gene needs to be turned off permanently to, not only enable a stem cell to become a brain cell, but also to make it the proper sire of a line of many brain cells. The same genes that got a cell to the right stage in development may need to shut down for it remain the right cell type.

2:18 Methylation, the chemical attachment at a certain point on the DNA chain of a methyl group (one carbon atom bonded to three hydrogen atoms), is a principle type of epigenetic regulatory change.

2:25 Methylation is the attachment of a methyl group to cytosine, one of the four bases that encode genetic instructions with the DNA chain. When the methylation occurs at a cytosine that falls next to a guanine, another of the four bases, the methylation will make it possible for other proteins to bind to the DNA chain such that the surrounding gene is silenced.

2:47 The methylation interferes with a process by which DNA forms a complex with proteins called histones to form chromatin, which in turn makes stretches of DNA available to the gene expression machinery upon receipt of the right signals.

4:11 While we inherit our DNA code from our parents, epigenetic changes are not passed on. When a sperm or egg cell is produced, all the epigenetic marks are wiped clean.  Thus, epigenetic fine-tuning of gene expression begins a anew with each person. Combine this with the fact that sunlight, cigarette smoke and the foods we eat make epigenetic changes, and we all become authors of our own gene code.

4:56  "Superfoods" like broccoli have linked to methylation status, and experiments months in mice have shown that diet can change the methylation status of specific genes (say those involved in cancer risk).    

5:19 An interesting area of research in epigenetics is looking at lifelong risk of certain diseases (like Type 2 diabetes) based on events and influences that occur while that person is still in the womb.

6:18 Dr. Korf said the UAB epigenetics symposium is being held now because recent meetings on the UAB School of Medicine strategic plan revealed that many researchers were working in this area independently, and would benefit from collaborations.

7:35 Among the examples of key epigenetics research efforts underway at UAB, David Sweatt is looking at at the potential role of epigenetic changes in learning and memory, TrygveTollefsboll at fundamental aspects of epigenetic biology and Molly Bray at the impact of epigenetic changes on lifelong obesity risk.

8:00 The field is in its infancy in terms of determining epigenetic changes and what drives them tissue by tissue in conjunction with environmental factors. What is truly exciting now is the emergence of extremely powerful tools, the bioinformatics and high-speed genetic analysis technologies, that are driving the field forward.  There will probably prove to be as many epigenomes as there are tissue types in the body.

9:14 Some of the most exciting near future advances are coming in the epigenetics of cancer.  Mounting evidence suggests that some of the changes that turn genes off contribute to the development of cancers.
Tracking epigenetic changes may have predictive value in looking will benefit from a therapy and who is at risk for a cancer.

9:33 It has now been shown that some drugs interact with epigenetic changes, which raises the possibility of using drugs to turn back on genes silenced by abnormal, epigenetic mechanisms as part of disease.